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spk08: Ladies and gentlemen, please stand by. Good day and welcome to the Cura Oncology third quarter 2022 earnings conference call. Today's conference is being recorded. Now I would like to turn the conference over to your host, Pete Despain, Senior Vice President of Investor Relations. Please go ahead.
spk12: Thank you, Jake. Good morning and welcome to Cura Oncology's third quarter 2022 conference call. Joining me on the call are Dr. Troy Wilson, our President and CEO, and and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Dr. Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kuro's filings with the SEC, which are available from the SEC or on the Kuro Oncology website, for information concerning risk factors that could affect the company. With that, I'll now turn the call over to Troy.
spk06: Thank you, Pete, and thank you all for joining us this morning. Today, we announced a $25 million equity investment from Bristol Myers Squibb priced at $18.25 per share. As part of the transaction, BMS will appoint a member to our Global Steering Committee and provide valuable strategic input into our global development strategy. Notably, we'll maintain full ownership and control of our programs and operations. We have very much appreciated our engagement with and feedback from our BMS colleagues who are leaders in the discovery and development of transformational cancer treatments. This equity investment strengthens the relationship between our organizations, and it provides us with key insights and expertise. We're pleased to have the confidence of the BMS team. We look forward to working with them to deliver innovative science with the potential to benefit patients. This morning we also announced a term loan facility from Hercules Capital, providing loan proceeds of up to $125 million, of which $10 million will be drawn immediately after closing. Hercules has a long history of investing in innovative biotechnology companies, and we are grateful for their support. With the $25 million equity investment from BMS and the $10 million initial draw from the Hercules term loan, We now have $462.8 million in cash pro forma for September 30th, 2022. Furthermore, if the term loan is fully drawn, proceeds from these two transactions together with our existing cash are expected to fund our current operating plan into 2026. These transactions augment our already strong balance sheet and they give us significant flexibility as we prepare to advance into the registration enabling portion of COMET-001 for zift amenib, initiate multiple combination studies for zift amenib in earlier lines of acute myeloid leukemia, and continue to expand and invest in our farnesyl transferase inhibitor programs. We were also proud to announce this morning that our abstract reporting updated data from COMET-001 has been accepted for an oral presentation at the upcoming American Society of Hematology annual meeting in New Orleans. The abstract, which will be published on the ASH website a bit later this morning, highlights the encouraging safety profile and clinical activity of Ziftomenib in patients with relapsed and refractory AML. The abstract includes 30 all-comer AML patients from the Phase Ia dose escalation portion of COMET001 and 24 NPM1 mutant or KMT2A rearranged AML patients from the Phase 1B portion, 12 patients dosed at 200 milligrams, and 12 patients dosed at 600 milligrams. We also enrolled an additional 18 patients in a Phase 1B extension at the 600 milligram dose. Note these patients are not included in the abstract, which was submitted back on August 2nd using an early summer data cutoff. We look forward to sharing a more mature data set, including preliminary data from an additional 18 patients in the Phase 1B extension during our oral presentation at ASH. We'll also be hosting an in-person investor event featuring two of the trial's investigators immediately following the oral session on December 10th. Please stay tuned for more details. Meanwhile, we await feedback from FDA on the recommended Phase 2 dose for Zifta-Medib as well as the protocol for the Phase II registration-directed portion of COMET-001. We also intend to initiate studies of ziftomenib in combination with standards of care in earlier lines of therapy in AML patients. We have designed these Phase I studies to assess the safety, tolerability, and therapeutic activity of ziftomenib in combination with various regimens, including venetoclaxonazacitidine, FLT3 inhibitors, and the combination of 7 plus 3. We're very excited about the potential for these combination studies to further unlock the value of ziftomenib for patients with acute myeloid leukemia. We anticipate initiating the Phase II registration-directed portion of COMET-001 and the first in a series of Phase I combination studies in frontline and relapsed refractory AML in the first half of 2023 pending FDA review of our recommended phase two dose protocols. We continue to have strong conviction in Ziftomenib and its potential to be a best-in-class menin inhibitor. Our confidence is supported by a growing body of clinical data, and we look forward to sharing an update on the program with you at ASHE. Now let's turn our attention to our farnesyl transferase inhibitor programs. We continue to view farnesyl transferase inhibition as a potentially valuable therapeutic and commercial franchise, one with potential to deliver multiple opportunities in oncology. Our initial therapeutic application of tipifarnib, our first-generation FSI as a targeted therapy, was via direct inhibition of the HRAS oncogenic protein. These pioneering efforts ultimately led to a breakthrough therapy designation award in for tibifarnib as a monotherapy in recurrent and metastatic HRS mutant head and neck squamous cell carcinoma. More recently, we've been building upon the encouraging monotherapy activity of tibifarnib with a focus on overcoming drug resistance. Late last year, we initiated the current head and neck study, which was designed to evaluate the combination of tibifarnib and alpelisib, an inhibitor of PI3 kinase alpha, in selected HNSCC patient cohorts. We believe that HRAS and PI3 kinase alpha are codependent oncogenes in HNSCC, and the combination of the two inhibitors has potential to provide improved antitumor activity relative to inhibition of either target alone. The initial cohort of the current head and neck study is comprised of patients with PIK3CA-dependent HNSCC. In August, we announced the first patient dosed in a second cohort comprised of patients with HRAS overexpression. Last week at the EORTC NCI AACR Molecular Targets and Cancer Therapeutics Symposium in Barcelona, we reported the first demonstration that the combination of tipifarnib and alpelisib can induce a durable clinical response in a PIK3CA-dependent HNSCC. A patient with stage 3 squamous cell carcinoma of the tonsil with a PIK3CA mutation and HRS overexpression has achieved a durable partial remission in current HN. The 35-year-old patient enrolled in the study after failing two prior treatments and experienced an 81% reduction in target lesions after just one cycle of tipifarnib and nalpelacib, followed by an 84% reduction after three cycles. The patient continues on study for more than 27 weeks as of last week's presentation. Treatment-related adverse events in current HN have been consistent with the known safety profiles of each drug and are manageable with no dose-limiting toxicities reported to date. Our team is now working to identify a recommended Phase II dose and schedule for the combination with a goal of determining the optimum biologically active dose for the PIK3CA cohort in mid-2023. Meanwhile, we've continued our efforts to demonstrate the potential for tipifarnib to drive durable responses as a monotherapy in recurrent and metastatic HRAS mutant HNSCC through our AIM-HN registration-directed trial. Although we continue to observe evidence of meaningful clinical activity in patients enrolled with AIM-HN, we've elected to close the trial to further enrollment due to significant feasibility challenges. We're currently evaluating the best way to harvest and use the clinical data from RUNHN, which formed the basis of our breakthrough therapy designation, along with the data from AIMHN to inform future development of the program. We'd like to take this opportunity to thank the patients, investigators, and study teams who have participated in the AIMHN study. It's important to note that given the significant overlap between patients with HRAS overexpression and HRAS mutation, HRAS mutant HNSCC patients in the United States may be eligible to enroll in the ongoing current HN study. Beyond HNSCC, we continue to elucidate the roles of FTIs in preventing or delaying the emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications. One of these emerging combination opportunities was unveiled earlier this year at the American Association for Cancer Research annual meeting. The preclinical data generated through a collaboration with Inserm support the potential of tipifarnib to prevent emergence of resistance to osimertinib and other potent EGFR inhibitors. Motivated by this significant opportunity, we've initiated a phase one study of tipifarnib in combination with osimertinib in EGFR mutant on small cell lung cancer and expect to dose the first patient later this quarter. We intend to perform initial clinical evaluation of tipifarnib and osimertinib to gather valuable experience and data while in parallel advancing KO2806, the lead development candidate in our next generation FTI program through IND-enabling studies. Last week at the triple meeting, our collaborators at NSERM presented a follow-up poster which extended their findings from EGFR to other oncogenic drivers. A copy of the poster is available on the CURA website. Based on these recent findings as well as our own internal translational research efforts, We continue to investigate combinations of FDIs with other potent targeted therapies in preclinical studies. We intend to evaluate KO2806 in several of these combinations, and we remain on track to submit an investigational new drug application for KO2806 later this quarter. With that, I'll now turn the call over to Tom Doyle for a discussion of our financial results.
spk10: Thank you, Troy, and good morning, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2022. Research and development expenses for the third quarter of 2022 were $25 million compared to $22.4 million for the third quarter of 2021. The increase in R&D expenses was primarily due to the increases in personnel cost and discovery stage programs. General and administrative expenses for the third quarter of 2022 were $11.6 million compared to $11.3 million for the third quarter of 2021. The increase in G&A expenses was primarily due to increases in personnel costs. Net loss for the third quarter of 2022 was $35.5 million compared to a net loss of $33.4 million for the third quarter of 2021. As of September 30, 2022, we had cash, cash equivalent, and short-term investments of $427.8 million compared to $518 million as of December 31, 2021. As adjusted for the $25 million equity investment from Bristol-Myers Squibb and the $10 million initial draw from the Hercules Loan Facility, Cura had, on a pro forma basis, $462.8 million in cash, cash equivalent, and short-term investments as of September 30, 2022. We believe that our cash, cash equivalents, and short-term investments, plus cash from our term-length facility from Hercules, if fully drawn, will be sufficient to fund our current operating plan into 2026, placing us in a position to deliver meaningful value inflection from each of our three programs. With that, I now turn the call back over to Troy.
spk06: Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated milestones for the remainder of 2022 and the first half of 2023. For ZIFTO-MANIB, oral presentation of the Phase 1 data from Comet 001 at ASH in December, and initiation of the Phase 2 registration-directed portion of Comet 001 and a Phase I combination study in frontline and relapsed refractory AML in the first half of 2023, pending FDA review of the recommended Phase II dose and protocol. For tipifarnib, the first patient dosed in the Phase I current lung study in combination with osimertinib in the fourth quarter of 2022, and determination of the optimum biologically active dose, or OBAD, for the PIK3CA cohort in the Phase I current head and neck study in combination with Alpelosib in mid-2023. And for KO2806, submission of the IND application later this quarter. With that, operator, we're now ready for questions.
spk08: Ladies and gentlemen, if you would like to ask a question, please signal by pressing star 1 on your telephone keypad. Keep in mind, if you are using a speakerphone, please make sure the mute is released so that signal can reach your equipment. Once again, for questions, star 1.
spk07: We'll pause for just a moment to assemble the queue. And we will begin first with Jonathan Cheng with SVB Securities.
spk01: Jonathan Cheng Hi, guys. Good morning, and thanks for taking my questions. First question on Ziphtomenib. Can you provide any color on the latest status of your regulatory interactions and the next steps here?
spk06: Jonathan Cheng Sure, Jonathan. Good morning, and thank you. So, at this point, the agency has everything that it needs from us. We're awaiting alignment with them on, as I indicated in the prepared remarks, the recommended phase two dose and the forward plan and protocol for the registration enabling portion of the study. We're on track. We're just in the holding period before the formal type C meeting. We have not yet had our type C meeting. It's upcoming. We're not giving specific guidance on the date of the meeting, but from our perspective, we're well prepared and everything's on track.
spk01: Got it. And second question, can you give us any color on how we should be thinking about data in the full ASH presentation versus data coming up in the abstract this morning? And I guess the decision to include the preliminary data on the 18 additional patients in the full ASH presentation.
spk06: Sure. So, take those two questions. They're related, but let's take them separately. So, the data that you'll see in the abstract, as I indicated in the prepared remarks, is data from the Phase 1a dose escalation portion, which was in all comers, and the initial 24 patients in the dose optimization portion of the Phase 1b. So that's what's in the abstract, and that data is relatively immature. It's as of an early summer cutoff. It'll show you clearly. I mean, as we've indicated, we continued dosing at 600 milligrams. I think you'll see clear activity, clear definition around the only safety and tolerability is going to be differentiation syndrome. For the ASH presentation, Jonathan, that's going to be a much more comprehensive update. There we will have rolled those initial patients on and included an additional 18 patients from the Phase 1B extension. What that gives us then is the initial 12 patients plus an additional 18 at the dose that we believe is going to be the recommended Phase 2 dose for the Phase 2 monotherapy registrational study. And as I've said in the past, our ability to use Ziftimenib, both from an ability to drive clinical activity as well as our ability to detect and to manage differentiation syndrome, which is the only really adverse event we see, has improved as the trial has gone on. So you may not see that in full, Jonathan, in the ASH abstract. Obviously, it's still a bit of time before the abstracts drop later this morning. That story will be much more fleshed out in the actual ASH presentation in December. And we were delighted that the conference organizers gave us an oral spot to be able to tell that story, along with the investor meeting that will come immediately afterwards.
spk01: Understood. Thank you. And just third question, if I may. can you discuss the rationale and considerations around the BMS purchase agreement and loan agreement that was announced this morning?
spk06: Sure. Yeah. So we've been actively engaged in discussions with large pharma about our programs, you know, for quite some time now. And, you know, there's a significant amount of interest in both programs. Obviously, we have a an upcoming data inflection point with Zipdomenib at ASH. We have been in discussions with our colleagues at BMS for some time now. They indicated a desire to draw closer, and as we fleshed out what that would look like, we didn't feel it was an appropriate time yet to potentially partner, but we did really like the idea of bringing, you know, we've got really sophisticated expertise on the BMS side in both solid tumors and liquid tumors. And bringing that into what is essentially our global steering committee, not a governance body, but an advisory body, allows us to make, we think, better decisions. And so what it does, Jonathan, is it further strengthens the relationship between CURA and BMS. We were very clear, and as I said, again, in the prepared remarks, we maintain full ownership of the programs, we maintain full control, but it really allows us to continue to deepen that relationship. The reason for the BMS investment and then putting the facility in place is we're looking at making investments across the portfolio. In ZIFTO-Meneb, we talked about it, the registrational study, we've got an extensive program planned in combinations We have the current HN study ongoing. We're going to be moving 2806 very shortly into phase one with an expansive combination strategy behind that. And we wanted to give ourselves the flexibility to be able to make development decisions that we think can create value for patients and ultimately shareholders. And to do that, we want to be obviously at all times in the very strongest positions. position. So we run the company pretty conservatively. We've said that consistently. This gives us cash into 2026, and yet it allows us to fully fund everything we've just walked through across those three different pillars of the business. It was a good time, we thought, with the engagement with BMS. It was a good time to make sure we could shore up the company's capital resources as we look into 23.
spk07: Understood. Thanks for taking my questions. Pleasure. Thank you, John.
spk08: We'll now hear from Peter Lawson with Barclays. Please go ahead.
spk11: Thanks for taking my questions. Troy, I don't know how much you can say, but this type C meeting with the FDA, is that a year-end event, a 2022 event? Yeah. financing, did they see all the men in data, so what we see at the ASH oral presentation, for instance?
spk06: Yeah, Peter, two good questions, and I think top of mind for a lot of folks. While not being specific as to the date, I can tell you it is our goal to try to have all of this wrapped up by ASH. So, we're not, you know, again, part of the reason we've been guarded about the FDA engagement is we're one of the first companies through Project Optimus, and the FDA is going to make its own determination, but we think we're in a very strong position. If things go as we hope they will, we should have everything we need by ASH. That would be our goal. I can't be more specific than that, but it's not, from a timing perspective, and right now we're just literally waiting for the calendar. We're not expecting that we would move into 2023. We'd be able to give you an updated ASH. As far as what did BMS see, you can assume that BMS saw a comprehensive data set, including both the rationale for the recommended Phase II dose, as well as the full data set, which will be profiled at ASH. Yes, you can assume that they saw that.
spk11: Great. Thank you so much.
spk07: Thanks for that. Our pleasure. Thank you, Peter. Next question will come from Roger Song with Jefferies.
spk05: Great. Thank you for taking the question. Congrats for the update. So a couple from us, I understand you won't be able to talk about the real data, but just the high-level Given you have been guided, this efficacy is as good, if not better, than your competitor. And we also know Index will have updated data at ASH as well. Just curious your comments around this guidance for both abstract and implementation, and particularly how do you anticipate your competitor's data at ASH as well?
spk06: Yeah, Roger, I want to be careful, particularly like, you know, within an hour or so of abstracts dropping, not to comment too much on our competitors' data. Let's let their data speak for themselves. You know, with regard to our data, I think the most important point will be the point that I made about at ASH, you'll see N equals, you know, potentially N equals 30 patients at the recommended phase two dose. As the trial has gone on, you know, initially we started with by seeing a higher percentage of KMT2A patients in the trial versus NPM1 relative to the epidemiology that we would have expected. As the trial has gone on, that has tilted such that we've seen, you know, an enrichment in NPM1 as we've moved from early in the 1B on into sort of later in the 1B. And I think in particular, again, I'll reiterate what I've said. The goal for registration is a 20% to 30% CRCRH rate, four to six months median duration of response. Transfusion independence is a key secondary endpoint. What we'll show you, I think, is a comprehensive data set at what we believe and what we have proposed to the agency is our recommended phase two dose. You'll see a full safety package. You'll see a full efficacy package. I think you'll have a very clear idea, as we do, as to how that's going to read through into not only the monotherapy registrational studies, but the combinations as well. So as soon as the abstracts are available, we'll be able to answer questions about ours. That's going to be data as of, again, an early summer data cut, a point in time. We're really directing people toward the full data presentation at ASH. I think our data set, Roger, will be, as I've said before, I would challenge anyone else to put out as much data at their recommended Phase 2 dose as we intend to. I think Zipdomenib will you know, we hope will look good in that context, in the context of a comprehensive data presentation. It'll look good in the abstract as well, I think, but obviously as the numbers go up, as the denominator increases, your confidence that you're going to translate into a registrational study goes up as well.
spk05: That's great. Thanks for the comment. And I think you raise a point in terms of the genotype. kind of between the KMT2A and the NPM1. Maybe question is do you see the consistent efficacy between those two genotype and how did that compare to the current therapy given you may start to see some different CRH and the implication for this is would you would FDA will require different null hypothesis for those two genotypes for the registration trial?
spk06: Yeah, it's a good question. So, let me take your question in reverse, your questions in reverse. To the best of our understanding, the FDA can use, you know, perhaps not identical, but a very similar null hypothesis in the two genotypes. And we've given a range of 10% to 15% CRCRH. That's probably even being a bit generous. But the reason for that, Roger, is there's no effective therapy for either of these two genotypes in the relapsed refractory setting. So then if you're looking for a CRCRH rate that is 20% to 30%, that gives you adequate powering to be able to detect a difference between the sample population and the null hypothesis so that you can distinguish the two. In a monotherapy study, you wouldn't expect those designs to look substantially different. In our experience, and we've commented on this along the way, the dose is the same for the two populations. Where we see a difference is we see a higher incidence and a greater severity of differentiation syndrome in the patients who have KMT2A rearranged leukemia. In our experience, that genotype is much more invasive. It's much more disseminated. It's a much more aggressive form of leukemia. And so when you induce those tumors to differentiate, you're getting kind of a broad-based differentiation syndrome. Now, we've developed strategies to mitigate that, first of all, to detect it, to see it coming, and then to mitigate it. And we'll talk about that at ASHE. I don't think we're going to talk, it's not in the context of the abstract, you won't see it there, but you will see it, you will see our strategies both in monotherapy, Roger, as well as in combination therapy at ASH.
spk05: Excellent. Thanks for the extensive comment on those two questions. I appreciate that. That's all from us.
spk07: Our pleasure. Happy to do it. Our next question will come from Lee Wacek with Cantor Fitzgerald.
spk00: Hi, good morning. Thank you for taking my questions, Troy. Maybe just first on the ASH data update, can you give us a sense of maybe the median follow-up for the 24 patients and those 18 additional patients? And then, you know, in terms of the combination trials, can you sort of talk about how quickly you may be able to move into the clinic in, you know, first half of next year in both the refractory and the frontline setting. And how should we think about the timeline here relative to your competitors?
spk06: Yeah, okay. Three good questions, Leigh. So, again, I don't want to get ahead of the abstract. We're right on the eve of the abstract. Remember that the patients in the abstract, we completed dosing in the phase 1B dose optimization. We announced that on our May earnings call. This abstract is as of an early summer data cut. For the additional 18 patients, those patients were dosed between May and August. And we have a number of patients on study you can just kind of roll it forward. We're still at a point, I mean, we have a significant phase one study here. When you look at the 1A, the 1B optimization, and the 1B extension, but that being said, it's still a phase one study. So I think the duration of response is still kind of coming into view. It's going to be an evolving number as patients stay on study. What I can tell you is we're not we're, I would say, optimistic, somewhere between optimistic and confident. I want to be careful which word I choose. That four to six months median duration of response is achievable with Zyft-Amedib, right? We're not seeing any warning signs that tell us that patients are rolling off. To the contrary, when we see responses, they're typically pretty durable in duration. But we're still talking about, you know, an anecdotal, you know, number of patients. In terms of starting the trials, that was your second question, if we get the green light from the agency here in the fourth quarter, you're really looking at three to four months before you probably dose the first patient. And that's really just because the sites have to review, the institutional review boards have to review the protocol. There's a number of steps that you have to step through, and basically you just get the machine going. It's not as simple as just flipping the switch back on because this is a substantive change from phase one going into a registration enabling phase two. But you can imagine our team, we have a great team. They're doing everything they can at risk to position the sites to be ready to go. But just to set expectations, that's why we're guiding to sort of first half of 2023 and And then the final question on the competition, you know, there's no question, at least if we talk about syntax, there's no question we're behind. And I've said this before. I think Zifto-Menib potentially represents the most potent, cleanest, most combinable menin inhibitor that we have thus seen clinical data for. We will do everything we can to catch up. But as we've seen with KRAS, as we've seen with other agents where ultimately you're going to end up in combination, what matters is who can get to the combinations, who can drive the best activity with the best safety. And I think what you'll see at ASH is ZIFTO-MEDEV is very well positioned in that regard. So we'll do everything we can to catch up to CINDEX and to stay abreast or ahead of our competitors. But at the end of the day, the best data is going to win. And, you know, I hear people get agitated about this, and they're not really following history. Look at the KRAS story. Look at how that's rolling out. Like, history just keeps repeating itself with these targeted therapies. Menin inhibitors, yes, they show remarkable activity as monotherapy. But if you want to offer patients the promise of a long-term durable remission, you want to put them into some form of combo, whether it's venetoclax, whether it's chemo. That's going to really give them the best chance for something approximating a cure. And I think you'll see where I think Ziptomenib stacks up very nicely in that regard.
spk00: Okay, great. Maybe just a quick question on TP, I guess monotherapy. Sure. Can you just give us a sense of, you know, how many patients that you've enrolled so far and what proportion of those patients that you can potentially, I guess, enroll into the current agenda study?
spk06: Yeah. So, we're not being specific, Lee. It's a good question. And we're being a little bit vague in terms of what we're doing. We do see, you know, compelling activity in the AMHN study. The challenge, as we've been clear with folks, is it's a rare population and the vast majority of patients with HRAS mutations are too sick to even enroll in the trial. So we face significant feasibility challenges, but it's about enrollment. It's not about either safety or activity of the drug. We've enrolled a significant number of patients, significant enough that we can confidently say we're seeing activity. But we're also trying to be good fiduciaries here at Cura. And as we look at the various investments that we could potentially make over the next couple of years in terms of maximizing value for shareholders, I think we've got to ask and answer hard questions. So what we're going to do, because we have, you know, probably more data in HRAS mutant patient head and neck squamous cell carcinoma than anyone in the world, we're going to do what we can to harvest that data. We've got a strong run HN data set. and we're going to see if there are potentially paths forward from a development and regulatory perspective. I don't want to say too much because I don't want to set expectations inappropriately, but our team is focused and knows what they have to do, and if and when it's appropriate, we'll come back to you with more information on the path forward for the monotherapy. You raise an important point, and that is, We were really pleased to see the patient who was profiled at the triple meeting. I can tell you our experience is, given that PIK3CA dysregulation is a mechanism of resistance to patients with HRAS mutations, the combination is a logical next step. Current HN is actually enrolling very nicely. Not surprisingly, you significantly expand the patient population. You're going to drive enrollment. We want to make sure that these patients have, particularly those in the U.S., have a place to go. And there's about an 80% overlap lead between HRAS overexpression and HRAS mutation. So it's our hope that for patients who have HRAS mutations, if they also qualify for overexpression, they will be eligible potentially to be included in the current HN study. Because ultimately, you know, the way we win is you put patients first. You have to be a good fiduciary, but we're trying to be very responsible and make sure that we can find a way to provide these patients appropriate care.
spk07: Thank you so much. Our pleasure. Tiago Potts with Credit Suisse has the next question.
spk02: Just a quick follow-up from you on Zipto. So as you look at the mix of patients between NPM1 mutant or KM22A rearranged, there's still some skepticism on the feasibility or the amount of patients on the NPM1 bucket, which would be potentially a little bit bigger. But it sounds like you're actually seeing a relatively healthy mix. What are the implications for that on building registrational cohorts? But we still get some questions around the commercial opportunity there, so it would be good to get any color. It sounds like you are seeing a healthy amount of NPM1 patients there.
spk06: Yeah, Tiago, it's a good question. So as the trial has gone on, we've seen the balance tilt in favor of more NPM1 patients, you know, in the numerator relative to the denominator. I think that's probably most notably driven by clinical activity. just to put it out there. I don't want to be specific as to numbers. Let's not get too far ahead of the data, but we feel confident in the feasibility of enrolling an NPM-1 mutant cohort. We also feel confident that we're seeing a favorable benefit-risk for the patients. And, again, you'll get a glimpse of this in the abstract. It's definitely going in the right direction. It's encouraging. You'll get a much more comprehensive update with those N equals 30 denominator patients at ASH.
spk07: Got it. Thanks for taking the question. Sure. Moving on to Phil Nadu with Cowan.
spk03: Good morning. Congrats on the progress. Thanks for taking our questions. We have two on ZIFTO and then one follow-up on AMHN. First on ZIFTO, we're curious about the Type C meeting. Why do you feel a Type C meeting is necessary? Had you always expected to have one? It seems like to sign off on a Phase 2 dose and a protocol, maybe a meeting wouldn't have been necessary. And then second, on the DS... It sounds like you're basically suggesting that the DS is going to look better at ASH than maybe what we see in the abstract. You've given, I think, two reasons why that could be. One is better management, and the other is different patient mix with more NPM1 patients. What would be the relative contribution in your mind to the improving DS rates that you're seeing over time?
spk06: Yeah, Phil, thanks for the two questions. So on the DS... You know, DS is a non-mechanism effect. It's a non-mechanism adverse event, obviously. Our ability to detect it, to see it coming, has greatly improved in terms of looking at inflammatory markers. And these were measures that we put in place as we came off clinical hold. Those measures have been effective. And it also, you know, the physicians, I think, have gotten more comfortable with their ability to manage differentiation syndromes. The differentiation syndrome is qualitatively different between the two genotypes. The NPM1 is more, in our minds, what people would characterize as a typical DS with other targeted therapies. The KMT2A is a bit of a different animal, and as I said, we think that's really due to two reasons. One is the nature of the disease, and the second is the nature of ziftomenib. Zipdomen in our experience is highly tissue penetrant. It really is able to get into all of the, I call it the nooks and crannies of the patients, and find those tumor cells in the tissue, in the lymphatic system, in the joints. And ultimately, the reason that may be important is if patients are relapsing, often they may be relapsing because there's residual AML hiding in their tissue. So that has implications for treatment. I think it's improving, Phil, frankly, because our ability to detect it and manage it has improved over time. With respect to your question about the FDA meeting, so we had a meeting with the agency to discuss the Phase 1b dose optimization. The agency considered that a Type B meeting, our one Type B meeting for an end of Phase 1. So, by default, if we were going to request a meeting, it was going to be a Type C meeting. We specifically requested a Type C meeting for the reason that if we don't, there really isn't any timeframe that the agency has to get back to us. A Type C meeting is a very, as people may know, it's a bounded, you know, choreographed engagement with the agency. You schedule a meeting in advance. You provide a briefing book. You know, typically the agency responds to the questions you've posed. So we did it really, Phil, to ensure that we would get questions directly on both the recommended phase two dose and the protocol in a timely manner. And I'll just remind people, because people really focus on the RP2D, it's not just the RP2D. Yes, that's important. It's probably, you know, one of the more important elements for moving forward. But this is our last opportunity before we have a pre-NDA meeting to engage with the agency, you know, with the exception of maybe getting breakthrough therapy designation or something like that. So you want to make sure you've got all your ducks in a row. Does the agency agree with you on the statistical plan? Do they agree with you on the companion diagnostics? We want to make sure that the agency is fully aligned with us on the design and execution of the Phase II trial, because after that it's go, you know, go, go, go. So this is really serving a dual purpose of closing out the very productive exercise on Project Optimus, and then making sure that we have alignment from the various directorates within the FDA on the design and execution of the Phase II monotherapy study, and then that rolls forward into the combination studies and so forth. So that's the reason for the Type C. And, you know, the agency wants to help sponsors. So we, you know, they have been very good partners throughout the process of development of Zipdomenib. They were extremely helpful in helping us get the program off clinical hold, and we're very much looking forward to wrapping this phase of it up and moving on into Phase II.
spk03: That's very helpful. And then just the last follow-up question on AMHN. Do you think there's sufficient power, given the number of patients that you've enrolled, or a sufficient number of patients enrolled for meaningful power on the trials endpoint? Is it possible that you could unblind the data and we actually get a positive result that supports filing?
spk06: Yeah, so the short answer to your question, Phil, is We wouldn't have phrased it as spending time harvesting the data for AIM and RUN if we didn't feel that there was potentially a path forward. Because of obvious, there are development and regulatory interactions that have to kind of stay behind the curtain. I don't want to say too much. But, you know, and I also want to be careful. I mean, we did close a trial prior to completion of enrollment for, you know, lack of feasibility. So I would say it's challenging, but potentially there's a way to harvest that data. And let us, we have some more work we need to do. Let us come back to you likely next year with some more information. Our team is working internally. And I'll have more to say. I appreciate that may be a little bit unsatisfying, but because of the strong signal we saw in RUN, because of the meaningful clinical activity we've seen in AIM, you know, potentially there's a way to harvest this data for patients, and that's really ultimately going to be our number one goal.
spk03: That's helpful. Thanks again for taking our questions. Sure.
spk07: Our pleasure.
spk08: And once again, ladies and gentlemen, for question star one, we'll now move to Wren Benjamin with JMP Securities.
spk09: Hey, good morning, guys. Thanks for taking the questions and congrats on the progress. Troy, I thought that the confirmatory trial design was more or less largely agreed upon, you know, with the FDA in the past. I think you had given parameters around what the confirmatory study could look like. Am I remembering that right? And, I mean, has there been any changes to those parameters that you had originally spelled out?
spk07: I'm sorry, Ren. The confirmatory study for – which study are we talking about?
spk06: For ZIFTO, you know, as we were – Oh, for ZIFTO. I remember – No. Yeah. Yeah. Yeah, yeah, yeah. So, no, no, no. So, if I left folks with that impression, then that was my error. So, what we gained alignment from in the meeting where – we discussed and agreed upon the Phase 1B dose optimization was that we would use endpoints in the Phase 1B optimization that were consistent with endpoints that would be used in a registration-enabling study. And that's exactly what we've done. And that's why I say, you know, I keep saying it over and over again, kind of what the bar to success is in terms of CR, CRH rate and so forth. This now, Ren, goes a step further. So does the agency agree on the null hypothesis we've selected? Does the agency agree they should agree, but does the agency agree on the manner in which we're handling differentiation syndrome if it arises? Those sorts of questions. There are still some outstanding questions. And again, you can, you know, to the question that Phil asked previously, you can always send your protocol to the agency, but the agency is not obligated to respond to you in 30 days. So if you really want to make sure that you're pushing timelines, it's important to to go through the formal process and schedule the meeting. And this is probably the most significant interaction on this program. And so we really also want to get the FDA's buy-in and make sure we do it right. Because the decisions that we've made that we're recommending to the FDA, they set the foundation for every future study. Not only the dose, but how we're handling DS, what we're seeing, the agency will look back on this phase one data package as foundational for the future development of Zift Amenib. So it's just good practice for sponsors to take time. If the FDA is willing to engage with you, take the time and do it. In my experience, having done this for a while, it might take you a month or two longer, but you may save yourself considerable pain and heartache down the road. So it's good to get the FDA spy in, and that's exactly what our team is doing. Got it.
spk09: Just switching gears to current HN, can you talk or provide a little bit more color on this patient with the durable response? How do you, you know, have you evaluated or is there a way to evaluate the relative contribution of TIPI versus a pellicid, you know, just any additional data?
spk06: Yeah, it's a good question, Ren. And the short answer is no. You know, it is anecdotal. I think the reasons that we are encouraged, we are encouraged first and foremost because we have been able to combine tipifarnib and alpelicib in a heavily pretreated population. with thus far manageable safety and expected adverse events. We're not seeing overlapping or cumulative toxicity. That was a big question mark. We shouldn't skip over that. Most of the time that people have tried to combine inhibitors of the MAP kinase pathway with inhibitors of the PI3 kinase pathway, they've found it's nearly impossible to combine because of the overlapping toxicity. hitting foreign cell transferase is not the same as hitting a MAP kinase pathway target in our experience. So that's encouraging. We are seeing evidence of sort of clinical activity, clinical benefit in other patients. We're right in the midst of dose optimization. And as we indicated in the poster, One of the challenges we have to address is the hyperglycemia that is induced by Alpelicib. It's well-known. It's seen in their labeled indication of breast cancer. But there are a number of mitigating steps that one can take that we really haven't done yet. Those include potentially scheduled changes using rapid-onset anti-hyperglycemics, you know, those sorts of things. I think this is, you know, the good news is we're seeing sort of as... As one of our physicians at the company says, we're seeing green shoots of activity. We just have work to do on dose optimization to see if we can identify an optimal biologically active dose that gives us a response rate that gives us a path forward then into registration of the combo. At that point, Ren, then I think we can do the proper study that identifies the individual contribution of the two components. But on a patient-by-patient basis, that's sort of too big an ask.
spk09: Got it. And then just finally for us with 2806, how are you guys going to go about selecting the ideal indications, let alone the ideal combinations to, you know, initially evaluate? And I remember we've talked in the past about, you know, a biomarker program either within Corel or just, you know, that you guys continue to evaluate that. Is that still kind of moving forward and is that being used?
spk06: Yeah, so two questions there, Ren, and let me answer them both and then peel them apart slightly. So in terms of identifying the optimal biologically active dose for 2806, we will do that in a biomarker-selected population. Consistent with Project Optimus, you'll look at PK and exposure, you'll look at pharmacodynamics, you'll look at safety and tolerability, and you'll look at any evidence of clinical activity. The FDA has been super clear about that, and we're going to make sure that we follow their guidance as they're expecting every sponsor to do. For your second question, it actually gets easier because we're positioning 2806 as an ideal combination agent for certain classes of targeted therapies. And let's just take the two that are visible to you right now. They are EGFR inhibitors and PI3 kinase alpha inhibitors. The good news, Wren, is we know those populations, right? You can look for T790M mutant. You can potentially look for exon 20 mutant. You can look for PI3 kinase alpha mutant. If you look at the NSERM poster, they have preclinical data that suggests the same synergy, the same ability of FTIs to blunt adaptive resistance also exists with ALK, with BRAF, and potentially with KRASP. Again, we know what those markers are. So as soon as we're able to determine the dose of 2806 that allows us to hit farnesyl transferase hard enough, if you will, you know, hard enough in air quotes, at least consistent with Project Optimus, then you roll it forward into biomarker-selected cohorts. And the beauty of that program is you're trying to do better than what pretty good targeted therapies are already doing. using the existing biomarkers, the existing patient populations. It makes that aspect of the development easier. And you can imagine a phase one that goes from a rapid monotherapy then into multiple combination cohorts. Great.
spk07: Thanks for taking the questions. Our pleasure.
spk08: And ladies and gentlemen, this will conclude your question and answer session. I'll turn the call back to Tori Wilson for closing remarks.
spk06: Great. Thank you, Operator. Thank you all once again for joining our call today. We'll be participating in the Credit Suisse Healthcare Conference next week, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Troy, or me. Have a good day, everyone. Thank you.
spk08: And ladies and gentlemen, this does conclude your conference for today. We do thank you for your participation, and you may now disconnect.
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